WO2003066574A1 - Derives d'amino-acides aromatiques et compositions medicamenteuses - Google Patents

Derives d'amino-acides aromatiques et compositions medicamenteuses Download PDF

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Publication number
WO2003066574A1
WO2003066574A1 PCT/JP2003/001081 JP0301081W WO03066574A1 WO 2003066574 A1 WO2003066574 A1 WO 2003066574A1 JP 0301081 W JP0301081 W JP 0301081W WO 03066574 A1 WO03066574 A1 WO 03066574A1
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Prior art keywords
group
nujol
phenyl
substituted
esi
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PCT/JP2003/001081
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English (en)
Japanese (ja)
Inventor
Hitoshi Endo
Yoshikatsu Kanai
Kenji Tsujihara
Kunio Saito
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Hitoshi Endo
Yoshikatsu Kanai
Kenji Tsujihara
Kunio Saito
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Application filed by Hitoshi Endo, Yoshikatsu Kanai, Kenji Tsujihara, Kunio Saito filed Critical Hitoshi Endo
Priority to US10/503,125 priority Critical patent/US7345068B2/en
Priority to EP03703151.5A priority patent/EP1481965B1/fr
Priority to JP2003565949A priority patent/JP4705756B2/ja
Priority to AU2003208105A priority patent/AU2003208105C1/en
Priority to KR1020047012112A priority patent/KR100948278B1/ko
Priority to CA2475434A priority patent/CA2475434C/fr
Publication of WO2003066574A1 publication Critical patent/WO2003066574A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Aromatic amino acid derivative and pharmaceutical composition are aromatic amino acid derivatives and pharmaceutical compositions.
  • the present invention relates to a novel aromatic amino acid derivative, and a pharmaceutical composition comprising the derivative as an active ingredient.
  • cancer chemotherapeutic agents exert a carcinostatic effect by directly inhibiting cellular DNA synthesis, and act effectively on tumors with active cell division.
  • existing cancer chemotherapeutic agents do not have sufficient selective toxicity to cancer cells and cause strong side effects.
  • a sufficient amount of cancer chemotherapeutic agent can not be administered to exert its anticancer effect.
  • cancer cells proliferate rapidly, resulting in abnormally enhanced uptake of essential amino acids that can not be produced by intracellular metabolism.
  • L-amino acid transporter which is a membrane protein required for intracellular uptake of neutral branched chain amino acids and aromatic amino acids containing many essential amino acids.
  • L—type amino acid transporter 1 (Kanai Y. et al., Journal of Biological Chemistry, 273, 23629 (1998)), and also in normal cells, L-type amino acid transporter (LAT2), a membrane protein that is essential for the uptake of essential amino acids. It has been confirmed that) exists (Japanese Patent Publication No. 2000-342270 etc.).
  • the present invention has been made in view of the above problems, and is a novel low molecular weight compound that strongly inhibits L ATI whose expression is specifically enhanced in cancer cells, and further, a novel low B compound that acts on L AT 2 It is an object of the present invention to find a molecular compound and provide a newly regulated cancer drug that suppresses cancer cell growth and a drug that exerts other effects.
  • the present inventors further selectively or nonselectively act on L AT 2 in order to develop a new regulated cancer drug capable of suppressing the growth of cancer cells by strongly inhibiting L AT 1.
  • various novel amino acid derivatives were synthesized, and their L ATI inhibitory activity, L AT 2P activity, and selectivity of L AT 1 / LAT 2 were examined.
  • the present inventors have completed the present invention by confirming that the aromatic amino acid derivative exhibits excellent L AT 1 P activity and suppresses proliferation of cancer cells.
  • R 1 represents a hydrogen atom or an amino protecting group
  • R 2 is a hydrogen atom or aryl, an aralkyl or alkyl group
  • R 3 is a halogen atom, an aryloamino group in which a 2 amino moiety may be substituted with a lower alkyl, a 3 lower alkyl, phenyl, phenyloxy, pyridyl, pyrimidinyl Is a phenyl group substituted with quinolyl, and each substituent in the phenyl group is further substituted with a halogen atom, cyano, hydroxy, carboxy, lower alkoxy, lower alkoxy, luponyl, phenyl, di-lower alkylamino or thiomorpholinyl 4-hydroxy, optionally substituted naphthyl or tetrahydro-naphthyl which may be substituted by lower alkoxy or lower alkylamino, and di-lower
  • a substituted heterocyclic group which may be substituted, and each substituent in the fused heterocyclic group is a halogen atom, hydroxy, lower alkyl Lower alkoxy, phenyl, di-lower alkylamino, lower alkoxy, bis-le
  • Y is O or N H
  • n is an integer of 0 to 5
  • an aromatic amino acid derivative represented by or a pharmacologically acceptable salt thereof represented by or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising the aromatic amino acid derivative of the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, in particular, a pharmaceutical useful as an L-amino acid transporter transporter. A composition is provided.
  • This inhibitor allows the transport of essential amino acids, which are one of the major nutrients of cancer cells.
  • -It is possible to inhibit (L AT 1) and cause the death of essential amino acids in cancer cells, which in turn can suppress the growth of cancer cells.
  • L AT 1 is possible to suppress angiogenesis associated with malignant tumors and angiogenesis associated with proliferative lesions of the retina such as diabetic retinopathy.
  • LAT2 is possible to suppress suppressive effects such as diseases associated with cell proliferation, such as various inflammatory diseases and excessive granulation during wound healing process.
  • the absorption of the toxic substance transported via transport system L for example, methylmercury etc.
  • FIG. 1 is a graph showing the growth inhibitory activity of cancer cells by the aromatic amino acid derivative of the present invention (Example 6).
  • FIG. 2 is a graph showing the growth inhibitory activity of cancer cells by another aromatic amino acid derivative (Example 9) of the present invention.
  • FIG. 3 is a graph showing the growth inhibitory activity of cancer cells by still another aromatic amino acid derivative (Example 15) of the present invention.
  • FIG. 4 is a graph showing the growth inhibitory activity of cancer cells by still another aromatic amino acid derivative (Example 17) of the present invention.
  • FIG. 5 is a graph showing the growth inhibitory activity of cancer cells by still another aromatic amino acid derivative (Example 4 9) of the present invention.
  • FIG. 6 is a graph showing the growth inhibitory activity of cancer cells in vivo by the aromatic amino acid derivative (Example 4 9) of the present invention.
  • any group capable of generally protecting an amino group may be used, and specifically, a silyl group such as alkoxycarbonyl, halogen Or lower substituted alkanoyl, cyclo lower alkyl alkoxy lower alkyl, carboxy lower alkanoyl, lower alkyl rubamoyl, And arylsulfonyl and the like.
  • Particularly preferred amino-protecting groups include t-butyschicarponyl, trifluoroacetyl, acetyl and the like.
  • lower means one having 1 to 6 carbon atoms unless otherwise specified.
  • alkyl group for R 2 a lower alkyl group is preferable, and specifically, methyl, ethyl, propyl and the like can be mentioned.
  • aralkyl group include benzyl and phenethyl.
  • aryl group include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and biphenyl.
  • Examples of the halogen atom of R 3 and X include fluorine, chlorine, bromine and iodine.
  • Examples of the aryloamino group of R 3 include benzoylamino, toluoylamino, naphthoylamino and the like, and among these, benzylamino is preferable.
  • the amino in the aryloamino group may be substituted with lower alkyl.
  • R 3 methoxy, ethoxy, propoxy and the like can be mentioned.
  • lower alkoxycarbonyl there may be mentioned methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like.
  • di-lower alkylamino include dimethylamino, getilamino, dipropylamino and the like.
  • Examples of unsaturated monocyclic heterocyclic groups containing N, O and Z or S in R 3 include furyl, chenyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl nore, imidazolyl, virazolyl, furazanyl, pyridyl, pyridazinyl And pyrimidinyl and virazinyl.
  • oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl and the like are preferable.
  • the cycloalkyl in R 3 includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Among them, cyclohexyl and the like are preferable.
  • Examples of di-lower alkyl group rubamoyl include dimethyl carbamoyl, cetyl carbamoyl, dipropyl carpamoyl and the like.
  • pyrrolidinyl-imidazolidinyl, pyrazolyl, pyrajul, birazoridinyl, piperidinyl, Piperazinyl, morpholinyl, piperidino, morpholino and the like can be mentioned. Among them, piperidinyl, morpholinyl, piperidino, morpholino, etc. are preferred! ,.
  • the optionally substituted fused heterocyclic group containing N, O and / or S in R 3 may be indolyl, isoindolyl, benzofuranyl, indolizinyl, chromonyl, quinolyl, isoquinolyl, quinolizinyl, There may be mentioned prill, indazolyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, benzomorpholinyl, carpazolyl, xanthenyl and the like. Among them, indolyl, benzofuryl, benzoxazolyl, purinyl, benzothiazolyl, chromonyl, quinolyl, benzomorpholinyl and the like are preferable.
  • Examples of lower alkoxy in R 3 include acetoxy, propionyloxy, butyryloxy and the like.
  • Examples of bisle and oral (lower) alkyl] amino include bis [chloromethyl] amino, bis [chloroethyl] amino, bis [fluoromethyl] amino, bis [fluoroethyl] amino and the like.
  • N-lower alkyl-N-hydroxy (lower) alkylamino examples include N-methyl-N-hydroxymethylamino, N-methyl-N-hydroxy-amino, N-methyl-N-hydro Roxypropylamino, N-ethyl-N-hydroxymethylamino, N-ethyl-N-hydroxyalkylamino, N-ethyl-hydroxypropylamino and the like can be mentioned.
  • compounds in which the unsaturated monocyclic heterocyclic group at 5 in R 3 is pyridyl, oxazolyl or thiazolyl, and the saturated or unsaturated monocyclic heterocyclic group in 6 are A compound which is piperidinyl, pyrimidinyl, isoxazolyl, pyridyl or furyl, and the unsaturated or partially saturated fused heterocyclic group in 6 is
  • R 3 is a phenyl group substituted with 3-phenyl, phenoxy, pyridyl, pyrimidinyl or quinolyl, and each substituent in the phenyl group is a halogen atom, a hydroxyl or a di-lower alkylamino.
  • n is an optionally substituted naphthyl group which may be substituted with 4 hydroxy or lower alkoxy; and an N and O containing unsaturated monocyclic heterocyclic group substituted with 5 phenyl or naphthyl.
  • each substituent in the monocyclic heterocyclic group may be further substituted with hydroxy; 6 alkoxy, famino, lower alkyl, di-lower alkylamino, lower alkoxycarbonyl, di-lower alkyl rubamoyl, phenyl or N It may be substituted by a saturated or unsaturated monocyclic heterocyclic group containing O, Z and S or S.
  • N, O and Z or S-containing unsaturated or partially saturated, fused heterocyclic groups each substituent in the fused heterocyclic group being a halogen atom, hydroxy, It is a compound which may be further substituted by lower alkyl, lower alkoxy, phenyl, di-lower alkylamino, lower alkoxy.
  • R 3 is a phenyl group substituted with 3 phenyl or pyridyl, and each substituent in the phenyl group may be further substituted with a halogen atom or di-lower alkylamino; Naphthyl group optionally substituted by hydroxy or lower alkoxy; 6 alkoxy, lower alkyl, lower alkoxycarbonyl, phenyl or substituted by saturated or unsaturated monocyclic heterocyclic group containing N, O and Z or S An optionally substituted N, O and Pino or S-containing unsaturated or partially saturated fused heterocyclic group, each substituent in the fused heterocyclic group being a halogen atom And hydroxy, lower alkyl, lower alkoxy, di-lower alkylamino, and compounds which may be further substituted by lower alkoxy.
  • R 3 is an N-, O- and / or S-containing unsaturated or partially saturated or heterocyclic heterocyclic group substituted with 6-phenyl.
  • R ⁇ t-BuOCO, R 2 CH 3 or R ⁇ CFaCO,
  • R 2 CH 3 embodiment
  • R ⁇ t-BuOCO, R 2 CH 3 or R ⁇ CFgCO,
  • Example XR 1 The intermediate of each example of NHR 3 is
  • Example R, R 2 R 3 Among these, Examples 6, 10, 17, 22, 23, 30, 32 to 40, 48, 49, 52 to 56, 58, 63, 65, 70 to 74, 81, 83, 85, 87, 89 90, 91, 93, 96 to: 100, 102, 103, 106, 108, 112 are preferred.
  • R la is an amino protecting group such as t-butoxycarbonyl or an acyl group such as trifluoroacetyl
  • R 2a is an alkyl, aralkyl or aryl group
  • R is a hydroxy group, an amino group or trifluoromethanesulfonyl Oxy group
  • R 2 is a hydrogen atom or an alkyl group
  • R 3 is a halogen atom, an alkyl group which may have a substituent, a aryl group, a heterocyclic group, a fused cyclic hydrocarbon group or Amino group
  • X is a hydrogen atom, a halogen atom, an alkyl group or an alkoxyl group
  • 1 is 0 or 1
  • m is 1 or 2
  • n is an integer of 0 to 5
  • Y has an oxygen atom or a substituent
  • N may be a reactive group such as a hydroxyl group, a halogen atom or
  • reaction of the compound of the formula (II) with the compound of the formula (III) has an adverse effect on the reaction of tetrahydrohydrofuran, dimethylformamide, etc. when (i) n is 1 to 5 and R and Z are hydroxy groups. Condensation reaction is carried out at a reaction temperature of 30 to 25 ° C.
  • n 1 -5, when R is a hydroxyl or amino group, and Z is a reactive group such as a halogen atom, tetra-n-butyl iodide in the presence or absence of a solvent such as dimethyl formamide or acetone.
  • the reaction is carried out in the presence or absence of a phase transfer catalyst such as ammonium or the like, in the presence or absence of a base such as carbonate, cesium carbonate or sodium hydride, at a reaction temperature of 25 to 100 3 ⁇ 4 Reaction, ( ⁇ ⁇ ⁇ ) 11 is 0,
  • R is Dorokishi group, when Z is dihydric Dorokishiboriru group,
  • R 3 is an optionally substituted phenyl group, an optionally substituted heterocyclic group, dichloromethane, black hole Holm, 1, 2- Jikuroroetan Carried out at a reaction temperature of 25 to 60 ° C with cupric acetate in the presence of a base such as pyridine, tolylamine or a mixture thereof and a molecular sieve 4A in a halogen-based solvent such as (Iv)
  • R is a trifluoromethanesulfonyloxy group, and is a reactive group such as a dihydroxyboryl group, in
  • the elimination reaction of the amino protecting group in the compound of the formula (la) is carried out by using an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, P-toluenesulfonic acid or the like alone or as a mixture thereof.
  • Reaction carried out at 50 ° C. Reaction carried out at a reaction temperature of 0 ° to 25 ° C. in a mixed solvent of water and tetrahydrofuran, etc. using a base such as lithium hydroxide and sodium hydroxide, Yowihitrimethylsilane or trimethyl chloride Using sodium monoiodide silane, acetonitrile, black mouth
  • the reaction is carried out in a solvent such as formaldehyde at a reaction temperature of 40 to 80 ° C.
  • the reaction temperature of 25 to 50 It can be suitably carried out by a deprotection reaction such as a catalytic hydrogenation reaction which is carried out at ° C. or a combination of these deprotection reactions.
  • the substituent in the compound of Formula (la) is arbitrarily converted (For example, when R 3 in Formula (I a) is substituted with a hydroxy group as in Example 57), If an amino group is present in R 3 of the formula (la) as in Examples 4 1 and 4 2 2 2 2 Alternatively, as shown in Example 43, when a hydroxyl group is present in R 3 , it may be converted to a halogen atom, or Example 9 6 to 1 1 1 1 When a halogen atom is present in R 3 of the formula (la) as in 0, these substituents are converted by a conventional method in organic synthesis reaction such as cross-coupling reaction of aryl group or heterocyclic group) Then, you may deprotect.
  • aromatic amino acid derivative of the present invention is in D- or L-form depending on the presence of asymmetric carbon atom.
  • Formulas (I) and (unless otherwise stated) All other formulas in this specification include such stereoisomers and mixtures thereof (eg racemic mixtures). Above all
  • L-shaped aromatic amino acid derivatives are preferred.
  • the aromatic amino acid derivative of the present invention may be in the form of a salt, and as the salt, pharmacologically acceptable salts such as alkali metal salts (sodium salt, potassium salt etc.), alkali earth metal salts (Calcium salts, magnesium salts etc.) Ammonium salts, salts with organic bases (trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, dibenzylethylenediamine etc), organic acids (acetic acid, benzoic acid, Salts with succinic acid, fumanoleic acid, maleic acid, lactic acid, citric acid, tartaric acid, dalconic acid, methanesulfonic acid, benzenesulfonic acid, formic acid, ⁇ -toluenesulfonic acid, trifluoroacetic acid etc., inorganic acids (hydrochloric acid, brominated acid) Salts with hydrogen acid, sulfuric acid, phosphoric acid, etc., amino
  • aromatic amino acid derivatives and salts thereof may be in the form of hydrate, solvate such as ethanolate.
  • the aromatic amino acid derivative of the present invention is useful as an L-type amino acid transporter inhibitor, LAT1, both LAT1 and LAT2, and an L-amino acid transporter inhibitor capable of inhibiting LAT2.
  • This L-type amino acid transporter has an action of suppressing the growth of cancer cells, an action of suppressing angiogenesis associated with proliferative lesions of the retina such as glucose neovascularization associated with malignant tumors and diabetic retinopathy, diseases associated with cell proliferation, , Suppressive actions such as inflammatory diseases, excessive granulation during wound treatment, absorption of toxic substances transported via transport system L, and control of distribution in the body, caused by enhancement of amino acid metabolism in cells. It is useful as a drug that is expected to have various effects such as hyperglycemia caused by hyperglycemia, atrophy of skeletal muscle due to physiological or various diseases, and a suppressive action of bone resorption.
  • aromatic amino acid derivative of the present invention can be administered, for example, orally, percutaneously or by injection.
  • Tablets, granules and capsules for oral administration can be prepared using conventional additives, for example, binders (eg syrup, gum arabic, gelatin, sorbitol, tragacanth or polybipyrolidon); fillers (eg lactose, sugar, corn starch Calcium phosphate, sonolevitol or glycine); lubricants (eg, magnesium stearate, talc, polyethylene glycol or silica); disintegrants (eg, potato starch) or wetting agents (eg, sodium lauryl sulfate). Tablets, granules and capsules may be coated by methods known in the field of conventional formulations.
  • binders eg syrup, gum arabic, gelatin, sorbitol, tragacanth or polybipyrolidon
  • fillers eg lactose, sugar, corn starch Calcium phosphate, sonolevitol or glycine
  • lubricants eg, magnesium stea
  • Liquid preparations for oral administration may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, and may be lyophilised which dissolves in water or other suitable solvents before use. Also as a preparation.
  • Liquid preparations may be prepared by conventional additives such as suspending agents (eg sorbitol, syrup, methyl cenollose, glucose syrup, gelatino-water-containing edible fat); emulsifiers (eg lecithin, sorbitan monooleate or gum arabic); non-water Additives (eg, almond oil, fractionated coconut oil or oily esters such as glycerin, propylene glycol or ethyl alcohol); preservatives (eg, methyl or propyl P-hydroxybenzoate or sorbic acid) and It may contain a flavoring agent or a coloring agent.
  • suspending agents eg sorbitol, syrup, methyl cenollose, glucose syrup, gelatino-water-containing edible fat
  • emulsifiers eg lecithin, sorbitan monooleate or gum arabic
  • non-water Additives eg, almond oil, fractionated coconut oil or oily esters such as glycer
  • the active ingredient When administered transdermally, the active ingredient is in the form of a cream, lotion or soft drink It is also good. Cream or ointment formulations which can be used as medicaments can be prepared by methods well known in the art.
  • injections can be produced by suspending or dissolving Compound (I) or a salt thereof in a suitable medium.
  • the injection may contain a local anesthetic, an adjuvant such as a preservative and a buffer, and the like.
  • the dose of the compound (I) of the present invention and a salt thereof varies according to the activity of the compound (I), patient's age, body weight, general health, sex, time of administration, route of administration, severity of disease. For example, usually about 10 to 5000 mg, preferably about 100 to 3000 mg, per adult, per day is suitably administered in 1 to 5 divided doses.
  • Example 17 This compound was used as a raw material in Example 17.
  • the oxazole derivatives used in Examples 9, 13, 17 and 40 were synthesized according to this method.
  • the reaction mixture was diluted with methylene chloride (200 ml), washed successively with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure.
  • the methyl amino acid methyl ester (2.37 g, 73%) was obtained as pale yellow crystals.
  • Example 33 This compound was used as a raw material in Example 33.
  • the benzoxazoyl derivatives used in Examples 6, 22, 23, 25, 28, 28 to 30, 38, 43, 62, 63, 65 were synthesized according to this method.
  • This compound was used as a raw material in Examples 45 and 55.
  • Example 48 This compound was used as a raw material in Example 48.
  • Example 50 The product was used as a raw material of Example 51 without purification.
  • the boronic acid derivative used in Example 50 was synthesized according to this method.
  • This compound was used as a raw material in Example 61.
  • Example 64 This compound was used as a raw material in Example 64. Also, the benzothiazole derivatives used in Examples 7 4 and 7 5 were synthesized according to this method.
  • Example 7-3 This compound was used as a raw material in Example 66. Also, the benzimidazonore derivative used in Example 7-3 was synthesized according to this method.
  • Production example 1 3 1) Using 3-aminosalicylic acid methyl ester hydrochloride and 2-methylthiopyrimidin-5-carboic acid hydrochloride as starting materials according to Preparation Example 2, 2- (2-methylthiopyrimidine-5-inole) Benzoxazole-7-carboxylic acid methyl ester was obtained as pale yellow crystals. ra. p. ⁇ ⁇ ⁇ ⁇ 190 ⁇ 191 " ⁇ , IR (Nujol) 1719 cm" 1 , APCI-MS m / z: 302 [M + H] +
  • Example 72 This compound was used as a raw material in Example 72.
  • reaction mixture was ice-cooled, water (20 ml) was added dropwise, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate.
  • the extracted organic layer is washed successively with water and saturated brine and then dried, and the solvent is evaporated under reduced pressure to obtain ( ⁇ ) -2-phenyl-1, 4-benzoxazin-8-methanol (397). mg, 89%) were obtained as a slightly orange oil.
  • This compound was used as a raw material in Example 71.
  • Example 80 This compound was used as a raw material in Example 80.
  • the 3-hydroxymethylflavone-8-methanol was synthesized by acetating 3-hydroxymethylflavone-8-carboxylic acid according to a conventional method and then reducing the carboxyl group after acetylation of the hydroxy group.
  • This compound was used as a raw material in Example 81.
  • Production example 1 8 The reaction of 3-boromomethylflavone-8-carboxylic acid ethyl ester with dimethylamine in a conventional manner followed by reduction was carried out to synthesize 3-dimethylaminomethylflavone-8-methanol. mp: 149. 51.5 ° C., IR (Nujol) 3448, 1627 cm “ 1 , APCI-MS m / z: 310 [M + H] + This compound was used as a raw material in Example 82 .
  • This compound was used as a raw material in Example 83.
  • furan -7-carboxylic acid methyl ester is dimethylated by an amino group in a conventional manner, and then the ester group is reduced with lithium aluminum hydride to give (5-dimethylamino-2- Phenyl) benzo [b] furan-7-methanol was synthesized.
  • Production example 2 5 8-Hydroxymethyl-3-methylflavone was treated with sulfonyl chloride to synthesize 8-chloromethyl-3-methylflavone.
  • This compound was used as a raw material in Examples 108 and 109.
  • Nt-Butoxycarboquinole-3,5-Jodo-tyrosine methyl ester 700 mg, 1. 28 mmol
  • Tris (dibenzylidene) Acetone) dipalladium 37 mg, 0. 04 mmol
  • trifenyl phosphine 69 mg, 0.26 ⁇ ol
  • the reaction mixture was heated and stirred at 50 ° C. for 10 minutes, and then tetramethyltin (0.39 ml, 2.
  • Example 90 This compound was used as a raw material in Example 90.
  • the target compound was synthesized according to Example 2 from N-trifluoroacetyl-3,5-Jodo-L-tyrosine methyl ester via the corresponding intermediate.
  • the target compound was synthesized according to Example 2 from N-trifluoroacetyl-3,5-Jodo-L-tyrosine methyl ester via the corresponding intermediate.
  • the target compound was synthesized according to Example 2 from the corresponding intermediate from N-trifluoroacetyl-3,5-dimethyl-L-tyrosine methyl ester.
  • Example 6 the target compounds of the following Examples 7 to 39 were synthesized from the corresponding intermediates from 3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester.
  • Example 1 9 1) mp: 112 to 114 :, IR (Nujol) 3269, 1746, 1706 cnf 1 APCI-MS m / z: 533 [M + H] +
  • the reaction solution was diluted with ethyl acetate (20 ml), the organic layer was separated, washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure.
  • Example 41 In the same manner as in 1) to 4) of Example 41, the target compound was synthesized from 3,5-dichloro-N-trifluoroacetylino-tyrosine methyl ester as a raw material.
  • the reaction mixture was diluted with ethyl acetate, the insolubles were filtered off (celite) and washed with ethyl acetate.
  • the filtrate was washed successively with 10% hydrochloric acid and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • the target compound was synthesized from the corresponding intermediate using 3, 5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester as a raw material.
  • N-trifnurooloacetyleno- 3-hydroxy-L-phenylenoalanine cetylesestole 159 mg, 0.521 mol
  • 2-naphthaleneboronic acid 186 mg, 1.08 mol
  • Molecular sieves-4A powder Pyridine (0.22 ml, 2.72 mmol) was added to a suspension of 204 mg) and cupric acetate (153 mg, 0.842 mmol) in methylene chloride (7 ml), and stirred at room temperature for 16 hours in an air atmosphere (without argon) did.
  • N-trifluoroacetyl-3- (4-hydroxy Noxy) -L-phenylalanine acetyl ester is used as a raw material to remove N-trifluoroacetyl-3- [4- (4- (methoxyphenoxy) phenoxy] -diphenylalanine ethyl ester by a conventional method.
  • the compound was protected to synthesize 3- [4- (4-hydroxyphenoxy) phenoxy] -L-phenyl / realanine.
  • the obtained solid is dissolved in tetrahydrofuran (1.2 ml) -water (0.6 ml), lithium hydroxide monohydrate (41 mg, 0.973 mmol) is added under ice-cooling and stirring, and reaction is carried out at the same temperature for 12 hours.
  • the reaction solution was diluted with water (2 ml), adjusted to pH 3-4 by addition of 1N HC1, added water (25 ml) and stirred at room temperature for 1 hour.
  • the precipitate was collected by filtration, washed with water and then dried under reduced pressure to give 3- [2- (2-naphthyl) ethoxy] -L-f; diurabanine (55 mg, 593 ⁇ 4) as colorless crystals.
  • Example 6 the corresponding intermediates from 3, 5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester are subjected to the following Examples 61 to 76 and Examples 80 to 8 respectively.
  • the target compound of 5 was synthesized.
  • the target compound of Example 39 was esterified by a conventional method to synthesize the target compound of Example 77.
  • the target compound of Example 78 was esterified by a conventional method to synthesize the target compound of Example 78.
  • the target compound of Example 61 was esterified by a conventional method to synthesize the target compound of Example 79.
  • Example 4 In accordance with the synthesis method of 1) of 7), Nt-butoxycarbonyl-3,5-diqu oral-L-tyrosine acetyl ester is used as a raw material to obtain N- 1-butoxycarbonyl-3,5-dicarbothioate. -0-[(3-Dimethylcarbamoylflavone-8-yl) methyl] -L-tyrosine Ethyl ester was synthesized.
  • Example 9 1 Method of 2) of Example 6 using 3, 5-di-c-O- 4-[(3-methylflavone-8-enole) methyl] amino-N-trifluoracetyl-L-phenylanine ethyl ester as a raw material
  • the target compound of Example 9 1 was synthesized according to the same manner as above.
  • the target compound of Example 9-1 was esterified by a conventional method to synthesize the target compound of Example 9-2.
  • the target compound of Example 9 3 was synthesized from N-trifluoroacetyl-3-hydroxy-L-phenylanine ethyl ester according to Example 4-9. Indicates the properties of intermediates and target compounds. 1) mp: 109.5-110.5 ° C, IR (Nujol) 3321, 1746, 1707, 1560 cm ⁇ ESI-MS m / z: 456 [MH]-
  • Example 1-9 of Example 9 using N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester and 5-bis [2- (benzyloxy) ethyl] amino-2-naphthaleneboronic acid as raw materials Then, 3- [5-bis [2- (benzyloxy) ethyl] amino-naphtho-2-ynore] -N-trifluoroacetyl-L-phenylanine ethyl ester was synthesized. Yellow oily substance, IR (Neat) 3330, 1725, 1715, 1600 cm- 1 , APCI-MS a / z: 715
  • Example 94 In the same manner as in 2) of Example 4-9, 3- [5-bis [2- (hydroxy) ethyl] amino-naphth-2-yl] -N-trifluoroacetyl-L-phene
  • the target compound of Example 94 was synthesized by hydrolyzing diuraranethyl ester.
  • Example 95 In the same manner as 2) in Example 49, 3- [5-bis [2- (chloro) ethyl] amino-naphtho-2-yl] -N-trifluoroacetyl-L-phenylanine
  • the target compound of Example 95 was synthesized by hydrolyzing the ethyl ester.
  • Example 96 1) According to 1) of Example 4-9, using N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (1.47 g, 4.82 mmol) as a raw material, 3- (3-bromophenoxy) -N -Trifluoroacetyl-L-phenylanine ethyl ester (1.59 g, 82%) was obtained as a colorless oil.
  • reaction solution is brought to room temperature, ethyl acetate is added, and the mixture is washed successively with saturated aqueous sodium fluoride solution, water and saturated brine, and dried.
  • the solvent is evaporated under reduced pressure.
  • Example 9 6 N-trifluoroacetyl-3- [3- (4-pyridyl) phenoxy] -L-phenylanine was hydrolyzed to give Example 9 6
  • the target compound of was synthesized.
  • Example 9 Example 9 to 1 0 3, Example 1 0 5 to 1 0 8 target compounds were synthesized The However, in Examples 97, 101 and 106, water-containing dimeticane was used as a solvent with sodium acetate as a base, using the corresponding borate in place of the tin compound.
  • Example 97, 101 and 106 water-containing dimeticane was used as a solvent with sodium acetate as a base, using the corresponding borate in place of the tin compound.
  • Example 97, 101 and 106 water-containing dimeticane was used as a solvent with sodium acetate as a base, using the corresponding borate in place of the tin compound.
  • Example 97, 101 and 106 water-containing dimeticane was used as a solvent with sodium acetate as a base, using the corresponding borate in place of the tin compound.
  • the hydrochloride salt of the target compound of Example 97 was synthesized by a conventional method.
  • the target compound of Example 103 was esterified by a conventional method to synthesize an ethyl ester (hydrochloric acid salt).
  • Example 1 0 7 1) colorless resinous substance, IR (Neat + CHC1 3 ) 3321 1719 1602 cm ⁇ ⁇ ESI-MS m / z '. 558 [MH]-
  • Nt-butoxycarbonyl-3-hydroxy-L-phenylalanine methyl ester (328 mg 4.82 ol) as a raw material according to 1) of Example 49, 3_ (4-bromophenoxy) -Nt-butoxycarbonyl L-phenylalanin methyl ester (547 mg, 94%) was obtained as a colorless oil.
  • the reaction mixture was allowed to room temperature, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium fluoride solution, water and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • the residue is purified by amino silica gel column chromatography (Chromatorex (registered trademark) H) (n-hexane / ethyl acetate-5) to give N-t-butoxycarponyl-3- [4- (2-dimethyla Minopyrimidine 5-yl) phenoxy] -phenylanine ethyl ester (121 mg, 42%) was obtained as a colorless oily substance.
  • Example 109 the target compound of Example 10 was synthesized from 3- (4-bromophenoxy) -Nt-butoxycarbonyl-L-phenylalanine methyl ester as a raw material via the corresponding intermediate. .
  • the physical properties of the intermediate and the target compound are shown.
  • Trifluoromethanesulfonic acid anhydride N-trifluoroacetyl -3-hydroxy-L-phenylanine ethyl ester (915 mg, 3. 00 ml) in pyridine (9 ml) solution under argon atmosphere with ice-cooling) 1. 51 ml was added dropwise over 5 minutes, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 16 hours.
  • the reaction solution was poured into ice water (500 ml) and extracted with ethyl acetate. The extract layer was washed successively with 10% aqueous hydrochloric acid, water and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was brought to room temperature, diluted with ethyl acetate and water, and extracted with ethyl acetate.
  • the extract layer was washed successively with water and saturated brine and dried, and the solvent was evaporated under reduced pressure.
  • Example 1 1 1 was synthesized by hydrolyzing N-trifluoroacetyl-3- (2-naphthyl) -L-phenylaranine ethyl ester. . mp: 220-224 ° C. (dec.), IR (Nujol) 3397, 1509 cm “ 1 , ESI-MS m / z: 290 [MH]-, Elemental analysis: C 19 H 17 N 0 2 ⁇ 0.5 H 2 Calculated as 0: C, 75. 98; H, 6. 04; N, 4. 66; Found: C, 76. 01; H, 5. 99; N, 4. 66 Example 1 1 2
  • Example 1 1 N-Trifluoroacetyl -3-trifluoromethanesulfonyloxy -L-phenylalaynetyl ester is used as a raw material according to Example 1 1 via the corresponding intermediate Two target compounds were synthesized. The physical properties of the intermediate and the desired product are shown.
  • DMS0 was added to each of the weighed test compounds, and a solution or suspension of 100 mM was prepared as a DMS0 stock. At the time of assay, this stock was diluted 1 000 times with a buffer solution described later to make the final concentration of the test compound 10 10 / M, and the final concentration of DMS 0 0.1.
  • the LAT 1 inhibitory activity of the test compound was determined as follows. Using human bladder cancer cell line T24 cells in which only LAT 1 is highly expressed, the uptake inhibitory activity of ““ C ”-L-leucine by each compound was measured, and it was defined as LAT 1 inhibitory activity.
  • The% inhibition was calculated by the following equation.
  • test compounds (2 of Example 6), 9, 7 and 49 (2)
  • DMSO DMSO
  • DMS0 DMSO
  • this stock was diluted with DMS0 to prepare a 1000-fold solution of the final concentration of each test compound, and each solution was diluted 100-fold with culture medium and one-tenth of the total volume was added.
  • T24 cells at the log growth stage were prepared at 1 ⁇ 10 3 cells / ml, aliquoted 900 ml each into a 24-well plate, and allowed to stand at 37 ° C. for 6 hours. After cell attachment, 100 ml each of a diluted solution of a test compound, which was prepared to have a final concentration of 10 times with a medium, was added to each well and cultured at 37 ° C. for 5 days. A medium containing 0.1% DMS0 was added to the test compound-free solution. After 5 days, the cells in the wells were detached by trypsin / EDTA treatment, collected by centrifugation at 1500 rpm for 5 minutes, suspended in a small amount of medium and counted on a hemocytometer.
  • The% inhibition was calculated by the following equation.
  • Inhibition% 100-(Number of cells with test compound added) / (Number of cells with no test compound added) X 100
  • Example 4 9 Transplanted with 1 X 1 0 6 amino sarcoma 1 8 0 cells ICR mice groin subcutaneous, test compounds hour after transplantation 2 4 (3 of Example 6), initiation of administration of 3)) of Example 4 9 Were administered intravenously over seven days.
  • the test compound was dissolved in physiological saline containing 10% of DMS0 and 10% of Tween 80 so as to be 100 mg / kg, and intravenously administered at 0.1 ml / g of body weight.
  • the tumor weight was measured, the growth inhibition rate was calculated from the following equation, and compared with that of the untreated control group.
  • Growth inhibition rate ( ⁇ / c) [1— (average tumor weight of test compound administration group average tumor weight of Z control group)] X 1 0 0 0
  • Example 6 and 3) of Example 4 9 showed a 52.2% and 41.3% growth inhibition rate at 100 mg / kg, respectively.
  • Nude mice 1 X 1 0 6 single T 2 4 cells were inoculated subcutaneously, to form a subcutaneous tumor.
  • Administration of the test compound (2 of Example 4 9) was started 5 days after the inoculation, and it was carried out for 10 days. It was administered continuously.
  • test compound was dissolved in physiological saline (containing 2% DMS 2 O) to a concentration of 2.577 mM, and 0.1 lm 1 was injected twice a day (morning and evening) into the tumor bed.
  • physiological saline containing 2% DMS 2 O
  • 0.1 lm 1 was injected twice a day (morning and evening) into the tumor bed.
  • saline containing 2% DMS22
  • the tumor diameter was measured before morning and evening administration.
  • Test Example 5 Examination method of LAT1 and LAT2 selectivity
  • RNA polymerase As RNA polymerase, T3, SP6 and T7 were used for hLATl, hLAT2 and h4F2hc, respectively.
  • Mmegaeru anesthetic solution (0. 2% MS- 222, was anesthetized by immersion in 0. 3% KHC0 3), were dissected abdominal with water, were removed oocyte mass under the peritoneum.
  • the excised oocyte clumps were shredded with pins, and then 0R2 medium containing 2 mg / mL collagenase (5 mM HEPES, 82.5 mM NaCl, 2 mM KC1, 1 mM MgCl 2) pH 7.5)
  • the cells are incubated at room temperature for about 30 minutes, washed with 0R2 medium, and Barth medium (10 mM HEPES, 88 mM NaCl, 1 mM KC1, 0.33 mM Ca (N0 3 ) 2 , 0.41 mM CaCl 2 ) 2, 0. 82 mM MgS0 4) 2. was transferred into 4 mM NaHC0 3, pH 7. 4 ).
  • cRNA As cRNA, hLATl cRNA and h4F2 hccRNA were injected into hLATl expression oocytes, and hLAT2 cRNA and h4F2 hccRNA were injected into equimolar mixture of hLAT2 expression oocytes.
  • choline 100 5 mM HEPES, 100 raM choline CI, 2 mM KC1, 1.8 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4.
  • 10 ⁇ M Uptake was carried out for 30 minutes by adding choline 100 containing 14 C-Leu and various concentrations of samples. Then, the cells were washed 6 times with 100 ° C. 100 ° C., and the oocytes were transferred to a vial one by one, 250 ⁇ l of 10% SDS was added, and shaken at room temperature for 1 hour to dissolve. After 1 hour, 3 mL of scintillator was added to the solution and the radioactivity was measured with a liquid scintillation counter. The inhibition rate was determined by the following equation using the average value of 8 to 10 cells.
  • Inhibition rate (%) 1 0 0-((radioactivity of test compound added well) I (radioactivity of non-added test compound Rowell) X 1 0 0
  • Example 6 and 3) of Example 49 were intravenously and orally administered as a group of 5 male mice (4 weeks old) of Sic: dDY.
  • the above compound was dissolved in saline containing 10% DMSO and 10% Tween 80 and administered at 1 Omg Zkg.
  • the control group received only the solvent.
  • the compound was suspended in distilled water and administered at 100 Omg Zkg.
  • the control group received only the solvent.
  • Example 77 was 69.3 mg / kg, and all the other compounds were 10 Omg Zkg or more.
  • LD 5n was similarly determined for BCH as a target, and was 30 Omg / kg or more.

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Abstract

Cette invention concerne des dérivés d'amino-acides aromatiques représentés par la formules générales (I) suivantes ou des sels de ces dérivés acceptables au plan pharmacologique. Dans cette formule, R1 représente hydrogène ou un groupe amino-protecteur ; R2 représente hydrogène, alkylaralkyle ou aryle ; R3 représente (1) halogéno, (2) aroylamino, (3) alkyle inférieur, phényle, phénoxy, etc. substitués phényle, (4) napthtyle ou tétrahydronaphtyle éventuellement substitué par hydroxy, alkoxy inférieur ou di(alkyle inférieur) amino, (5)un groupe hétérocyclique monocyclique insaturé renfermant un N-, S, O- et/ou S substitué par un alkyle inférieur, un phényle, un napthyle ou un tétrahydroquinolyle, ou (6) un groupe hétérocyclique fusionné contenant un N-, O- et/ou S-, qui peut être saturé ou partiellement insaturé, éventuellement substitué par oxo, carboxy, amino, alkyle inférieur, etc. ; X représente halogéno, alkyle ou alkoxy ; Y représente hydrogène ou azote ; 1 vaut = ou 1 ; m vaut 0, 1 ou 2 ; et n est un entier compris entre 0 et 5. Ces composés inhibent un vecteur (LAT1) d'amino-acides essentiels qui constituent l'un des principaux nutriments de cellules cancéreuses et induit un épuisement des amino-acides essentiels dans les cellule cancéreuses, ce qui inhibent la prolifération desdites cellules.
PCT/JP2003/001081 2002-02-07 2003-02-03 Derives d'amino-acides aromatiques et compositions medicamenteuses WO2003066574A1 (fr)

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US10/503,125 US7345068B2 (en) 2002-02-07 2003-02-03 Aromatic amino acid derivatives and medicinal compositions
EP03703151.5A EP1481965B1 (fr) 2002-02-07 2003-02-03 Derives d'amino-acides aromatiques et compositions medicamenteuses
JP2003565949A JP4705756B2 (ja) 2002-02-07 2003-02-03 芳香族アミノ酸誘導体及び医薬組成物
AU2003208105A AU2003208105C1 (en) 2002-02-07 2003-02-03 Aromatic amino acid derivatives and medicinal compositions
KR1020047012112A KR100948278B1 (ko) 2002-02-07 2003-02-03 방향족 아미노산 유도체 및 의약 조성물
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WO2005074996A3 (fr) * 2004-01-30 2006-01-05 Xenoport Inc Transporteur de lat1 exprime dans des cellules de la barriere hemato-encephalique
WO2005074996A2 (fr) * 2004-01-30 2005-08-18 Xenoport, Inc. Transporteur de lat1 exprime dans des cellules de la barriere hemato-encephalique
US7517910B2 (en) 2004-03-30 2009-04-14 Takeda Pharmaceutical Company Limited Alkoxyphenylpropanoic acid derivatives
JP4859665B2 (ja) * 2004-03-30 2012-01-25 武田薬品工業株式会社 アルコキシフェニルプロパン酸誘導体
EP2253315A1 (fr) 2004-03-30 2010-11-24 Takeda Pharmaceutical Company Limited Dérivés d'acide alkoxypropanoique
JPWO2005095338A1 (ja) * 2004-03-30 2008-02-21 武田薬品工業株式会社 アルコキシフェニルプロパン酸誘導体
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JP4705756B2 (ja) 2011-06-22
AU2003208105B2 (en) 2009-04-02
EP1481965B1 (fr) 2015-07-29
CN1293042C (zh) 2007-01-03
EP1481965A4 (fr) 2007-08-08
CA2475434A1 (fr) 2003-08-14
JPWO2003066574A1 (ja) 2005-05-26
CA2475434C (fr) 2011-04-05
AU2003208105A1 (en) 2003-09-02
KR20040105712A (ko) 2004-12-16
KR100948278B1 (ko) 2010-03-18
CN1630632A (zh) 2005-06-22
AU2003208105C1 (en) 2009-08-13
US20050119256A1 (en) 2005-06-02
US7345068B2 (en) 2008-03-18

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